A tracer kinetic model for 18F-FHBG for quantitating herpes simplex virus type 1 thymidine kinase reporter gene expression in living animals using PET.

Reporter probe 9-(4-18F-fluoro-3-[hydroxymethyl]butyl)guanine (18F-FHBG) and reporter gene mutant herpes simplex virus type 1 thymidine kinase (HSV1-sr39tk) have been used for imaging reporter gene expression with PET. Current methods for quantitating the images using the percentage injected dose per gram of tissue do not distinguish between the effects of probe transport and subsequent phosphorylation. We therefore investigated tracer kinetic models for 18F-FHBG dynamic microPET data and noninvasive methods for determining blood time-activity curves in an adenoviral gene delivery model in mice. METHODS: 18F-FHBG (approximately 7.4 MBq [approximately 200 microCi]) was injected into 4 mice; 18F-FHBG concentrations in plasma and whole blood were measured from mouse heart left ventricle (LV) direct sampling. Replication-incompetent adenovirus (0-2 x 10(9) plaque-forming units) with the E1 region deleted (n = 8) or replaced by HSV1-sr39tk (n = 18) was tail-vein injected into mice. Mice were dynamically scanned using microPET (approximately 7.4 MBq [approximately 200 microCi] 18F-FHBG) over 1 h; regions of interest were drawn on images of the heart and liver. Serial whole blood 18F-FHBG concentrations were measured in 6 of the mice by LV sampling, and 1 least-squares ratio of the heart image to the LV time-activity curve was calculated for all 6 mice. For 2 control mice and 9 mice expressing HSV1-sr39tk, heart image (input function) and liver image time-activity curves (tissue curves) were fit to 2- and 3-compartment models using Levenberg-Marquardt nonlinear regression. The models were compared using an F statistic. HSV1-sr39TK enzyme activity was determined from liver samples and compared with model parameter estimates. For another 3 control mice and 6 HSV1-sr39TK-positive mice, the model-predicted relative percentage of metabolites was compared with high-performance liquid chromatography analysis. RESULTS: The ratio of 18F-FHBG in plasma to whole blood was 0.84 +/- 0.05 (mean +/- SE) by 30 s after injection. The least-squares ratio of the heart image time-activity curve to the LV time-activity curve was 0.83 +/- 0.02, consistent with the recovery coefficient for the partial-volume effect (0.81) based on independent measures of heart geometry. A 3-compartment model best described 18F-FHBG kinetics in mice expressing HSV1-sr39tk in the liver; a 2-compartment model best described the kinetics in control mice. The 3-compartment model parameter, k3, correlated well with the HSV1-sr39TK enzyme activity (r2 = 0.88). CONCLUSION: 18F-FHBG equilibrates rapidly between plasma and whole blood in mice. Heart image time-activity curves corrected for partial-volume effects well approximate LV time-activity curves and can be used as input functions for 2- and 3-compartment models. The model parameter k3 from the 3-compartment model can be used as a noninvasive estimate for HSV1-sr39TK reporter protein activity and can predict the relative percentage of metabolites.     

Reproducibility of 18F-FDG microPET studies in mouse tumor xenografts.

(18)F-FDG has been used to image mouse xenograft models with small-animal PET for therapy response. However, the reproducibility of serial scans has not been determined. The purpose of this study was to determine the reproducibility of (18)F-FDG small-animal PET studies. METHODS: Mouse tumor xenografts were formed with B16F10 murine melanoma cells. A 7-min small-animal PET scan was performed 1 h after a 3.7- to 7.4-MBq (18)F-FDG injection via the tail vein. A second small-animal PET scan was performed 6 h later after reinjection of (18)F-FDG. Twenty-five sets of studies were performed. Mean injected dose per gram (%ID/g) values were calculated from tumor regions of interest. The coefficient of variation (COV) from studies performed on the same day was calculated to determine the reproducibility. Activity from the second scans performed after 6 h were adjusted by subtracting the estimated residual activity from the first (18)F-FDG injection. For 7 datasets, an additional scan immediately before the second injection was performed, and residual activity from this additional delayed scan was subtracted from the activity of the second injection. COVs of both subtraction methods were compared. Blood glucose values were measured at the time of injection and used to correct the %ID/g values. RESULTS: The COV for the mean %ID/g between (18)F-FDG small-animal PET scans performed on the same day 6 h apart was 15.4% +/- 12.6%. The delayed scan subtraction method did not produce any significant change in the COV. Blood glucose correction increased the COV. The injected dose, tumor size, and body weight did not appear to contribute to the variability of the scans. CONCLUSION: (18)F-FDG small-animal PET mouse xenograft studies were reproducible with moderately low variability. Therefore, serial small-animal PET studies may be performed with reasonable accuracy to measure tumor response to therapy.     

Use of the abdominal aorta for arterial input function determination in hepatic and renal PET studies.

A method using the activity in the abdominal aorta of human and animal subjects to noninvasively estimate blood-pool input function in dynamic, abdominal PET scans is proposed and validated in this paper. Partial volume effects due to the aorta's dimensions are corrected by a semi-automated algorithm based on the transaxial resolution in the reconstructed images. The technique was validated by comparing PET measurements of abdominal aortic activity to well counter measurements of arterial blood samples (eight canine renal studies) and to PET measurements of left ventricular cavity activity (eight human hepatic studies). In renal studies, correlation analysis of the areas subtended by the two input functions yielded an essentially unitary slope (1.03 +/- 0.09), with high correlation (R2 greater than 0.95, p less than 0.001). In hepatic studies, similar values (0.99 +/- 0.03 and R2 greater than 0.85, p less than 0.001) were found. Correlation of the blood flow estimates based on the two input functions and a two-compartment model produced slopes of 1.07 +/- 0.16 and 1.03 +/- 0.07, and correlations of (R2 greater than 0.98, p less than 0.001) and (R2 greater than 0.97, p less than 0.001) for the renal and hepatic studies, respectively. We conclude that noninvasive, accurate measurements of the arterial input function by dynamic PET imaging are possible and represent a clinically viable alternative to arterial blood sampling.     

Classifying choledochal cysts using hepatobiliary scintigraphy

PURPOSE: This retrospective study was designed to classify choledochal cysts on the basis of the findings of hepatobiliary scintigraphy. METHODS: Twenty-one patients with choledochal cysts (15 female, 6 male; mean age, 20 years) proved on the findings of endoscopic retrograde cholangiopancreatography (ERCP) or surgery and histopathologic analysis were included in the study. Two nuclear medicine physicians, blinded with regard to cholangiographic and operative details, were asked to review and to classify the type of choledochal cyst seen on the hepatobiliary scan. Later, scintigraphic results were compared with ERCP and surgical findings for a reference standard. RESULTS: The findings of hepatobiliary scintigraphy correlated with ERCP and surgical findings in 18 of 21 cases (86%). Scintiscans correctly identified all type 1 cysts (12/12). The sensitivity of scintigraphy in diagnosing type 4 cysts was 66% (6 of 9 cases). It underestimated the intrahepatic extent of disease in type 4a biliary cysts (37%). CONCLUSION: This study illustrates the utility of hepatobiliary scintigraphy in diagnosing type 1 and 4 choledochal cysts.     

Lipoprotein(a) as an independent risk factor for coronary artery disease in patients below 40 years of age

Coronary artery disease has assumed alarming proportions in Indians and often affects people at younger age. Traditional risk factors fail to explain the high incidence of disease. Although lipoprotein(a) has been shown to be a powerful risk factor for atherosclerosis, there is very limited data with regard to its significance in premature coronary artery disease. The present study was therefore undertaken to assess lipoprotein(a) levels and its role as a marker of coronary artery disease in patients below the age of 40 years. Lipid profile and lipoprotein(a) levels were estimated in 50 patients of angiographically proven coronary artery disease and an equal number of age-matched healthy controls. There was no significant difference in the family history of coronary artery disease, body mass index and waist-hip ratio between the two groups. Total plasma cholesterol, triglyceride and LDL-cholesterol levels were significantly higher and HDL-cholesterol significantly lower in patients as compared to controls. In patients of coronary artery disease, mean lipoprotein(a) levels, measured by ELISA method, were 35.0 +/- 32.4 mg/dL and the median was 26.7 mg/dL. These values were significantly higher than the mean of 20.3 +/- 17.0 mg/dL (p < 0.002) and the median of 13.8 mg/dL (p < 0.015) in controls. Multiple regression analysis, to assess the influence of various risk factors, showed that low HDL-cholesterol (odds ratio 4.62, 95% CI 1.84-11.60; p < 0.015) and elevated lipoprotein(a) levels (odds ratio 3.06, 95% CI 1.24-7.55; p < 0.001) were independent risk factors, whereas high total cholesterol and triglyceride levels did not have any independent influence on premature coronary artery disease. Our data thus suggest that lipoprotein (a) levels are elevated and constitute an independent risk factor in patients with premature coronary artery disease below 40 years of age.     

Effect of Immunosenescence on the Induction of Cardiovascular Disease Pathogenesis: Role of Peripheral Blood Mononuclear Cells

It is well established that the immune potential declines with age. However, there is a great paucity of information regarding role of monocytes in elderly suffering from cerebrovascular accident. This present study was undertaken to investigate if the functions of peripheral blood mononuclear cells have any correlation to the manifestation of an age-associated cerebrovascular disorders: myocardial infraction, cerebrovascular (infract & hemorrhage). An age-associated inhibition in the production of interleukin-1 (IL-1) by monocytes was observed while the production of nitric oxide (NO) remained unaltered in the response of monocytes, obtained from normal elderly donors, to Lipopolysaccharide (LPS) treatment in vitro. Cerebrovascular pathologies were found to be associated with an augmentation of IL-1 production by monocyte, while NO production was augmented in case of CVA (hemorrhage) and MI. Trace element copper was found to be lower in the serum of patients suffering from CVA, while concentration of zinc was found to be elevated in serum compared to these trace elements in normal adults. Thus these factors are likely to play a role in the pathogenesis of age-related cerebrovascular disorders.